In a relatively large number of cases, an infectious agent, such as Plasmodium or influenza, escapes a previous acquired (protective) immune response by changing one or more of its immune response inducing agents. Because of this, a previous acquired (protective) immune response, for example through vaccination or a previous infection, would be no longer suffice to control the establishment of the infectious agent.
In a number of cases, the (protective) immune response inducing agents, or antigens, are one or more surface proteins of the infectious agent and the changes involve amino acid substitution in these surface proteins. Such substituted proteins can be referred to as protein variants or polymorphic proteins of the immune response inducing agent or antigen.
The amino acid substitutions are in general limited to a specific subset of amino acid positions, because biological function(s) of the (protective) immune response inducing protein. For example, if the biological function of the (protective) immune response inducing protein is attachment to the outer wall of a host cell, the subset of amino acid positions which can be substituted in order to escape the immune system of the host is limited to those amino acid positions not affecting the attachment.
Further, because of the associated biological function(s), the number of possible amino acid substitutions at a specific amino acid position is limited.
For example, substitution of an acidic amino acid, such as aspartic acid (Asp), for a polar amino acid, such as serine (Ser), could affect the function of the immune response inducing protein and could therefore be not a suitable amino acid substitution for the infectious agent to escape the immune system of the host.
Furthermore, there appears to be a linkage, or correlation, between certain specific amino acid substitutions at specific positions of the antigen. In other words, the presence of, for example, an alanine (Ala) at a certain position in the antigen can be linked or correlated with the presence of, for example, a glycine (Gly) at a nearby or remote amino acid position in the antigen.
However, although the number of possible amino acid substitutions in a (protective) immune response inducing protein is limited, the number of possible variants of this protein remains still very high.
An example of this is the immunogenic hemagglutinin (HA) surface glycoprotein of the viral infectious agent influenza. The possible substitutable amino acid positions in this glycoprotein are so high that each year the most prevalent (regional) protein variants of HA have to be selected to provide an effective influenza vaccine for only that year.
Another example is the PfAMA-1 protein of the malaria causing infectious agent Plasmodium falciparum. 
Malaria is estimated to cause up to 500 million clinical cases and 2 million deaths annually. Most of the severe morbidity and mortality occurs through infection with Plasmodium falciparum in young children and pregnant women of sub-Saharan Africa.
Several potential (protective) immune response inducing agents have been identified for vaccine development, one of these being Plasmodium falciparum Apical Membrane Antigen 1 (PfAMA1 or AMA1), encoded by a single copy gene.
Evidence from rodent and non-human primate malaria models shows that antibody responses to AMA1 can reduce levels of infection and that antibodies to AMA1 inhibit asexual parasite multiplication in vitro.
In endemic areas the immune system generates anti-AMA1 antibodies in response to infection and these may correlate with protection.
AMA-1 (FIG. 1) is an 83 kDa protein comprising a large N-terminal ectodomain, a transmembrane region and a approximately 50 amino acid C-terminal cytoplasmic tail. The ectodomain contains 16 conserved cysteine residues that form eight intramolecular disulphide bonds defining a potential three domain structure. Recent crystal structures for AMA1 confirms this three domain structure, but suggests there is considerable interaction between the domains.
Antibodies to AMA1 block merozoite invasion of erythrocytes, merozoite reorientation at the erythrocyte surface, block proteolytic processing, and asexual blood stage parasites devoid of AMA1 appear not to be viable, suggesting that AMA1 provides a critical and non-redundant biological function during erythrocyte invasion.
AMA1 is also present on sporozoite stages of development suggesting vaccination with AMA1 may target more than just asexual erythrocytic development.
However, similar to hemagglutinin (HA) of influenza, AMA1 is known to be liable to amino acid substitutions providing an escape from an earlier acquired (protective) immune response.
This is exemplified by immunization studies in rabbits showing that, although antibodies obtained to PfAMA1 from one strain of malaria inhibit the growth of the homologous strain well, other strains are inhibited to a variably lesser degree. This suggests that PfAMA1 amino acid substitutions or polymorphism may diminish the efficacy of PfAMA1 based vaccines.
An rather obvious vaccine strategy against an infectious agent, such as influenza or Plasmodium, would be to include all known, or even all theoretically possible, protein variants or polymorphic forms of an antigen in one vaccine preparation in order to induce an effective (protective) immune response against all known, and even future, variants or polymorphs of the infectious agent.
However, such vaccine strategy would be rather unpractical or even impossible because of the large number of protein variants or polymorphic forms involved. Only for Plasmodium falciparum, already more than 300 different protein variants or polymorphic forms of the AMA1 protein are known. As a consequence, a vaccine preparation effective against only the known Plasmodium falciparum polymorphs would already comprise more than 300 protein variants.
Such vaccine preparations are not only difficult, laborious, and expensive to produce, even using the present days recombinant DNA technologies, their therapeutic effectiveness in inducing an immune response would also be questionable. When presented in a single vaccine preparation to the immune system, some protein variants, or parts thereof, would inherently be more immunogenic thereby inhibiting, or even preventing, the development of an immune response against less immunogenic protein variant or parts thereof.
Further, such vaccine preparation, comprising all known variants of an antigen, would probably not be effective against future strains of the infectious agent which are likely to develop because of the evolutionary pressure of such vaccine preparation.